Hypertension and cardiovascular diseases are serious health problems for many individuals in the industrialized world. Atrial natriuretic peptide (ANP) is an endogenous and potent hypotensive hormone that elicits natriuretic, diuretic, vasorelaxant, and antiproliferative effects, important factors in the control of blood pressure and cardiovascular homeostasis. One of the principal loci involved in the regulatory action of ANP is the guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), whose ANP-binding and guanylyl cyclase activities vary remarkably in different tissues. However, the molecular basis of the functional expression and regulation of Npr1 gene (coding for NPRA) are not well understood. To further understand the biological role(s) played by NPRA, we will study the physiological function(s) using Npr1 gene-targeted mutant mouse models, which we have established at our facility. Our fundamental hypothesis is that the absence of Npr1 gene expression in intact animals in vivo renders unopposed powerful sodium-retaining, vasoconstrictive, proinflammatory, and proliferative systems;whereas, overexpression of Npr1 gene exerts physiological effects that are natriuretic, vasodilatory, anti-inflammatory, and antiproliferative in nature. To accomplish the objective of this proposal, we will integrate genetic information at the molecular level, with biochemical information at the cellular level, and physiological information at the whole-animal level, resulting in a vertically integrated molecular-physiological strategy. We will exploit the power of molecular genetics techniques to answer cellular, biochemical, and pathophysiological questions in intact animals in vivo so as to arrive at conclusions that are definitive and physiologically relevant. The information obtained from the above lines of investigation will provide the means to test directly the efficacy and impact of Npr1 gene dosage and null mutation on ANP/NPRA-mediated biological responses. Progress in this field of research will significantly strengthen and advance our knowledge of genetic and molecular approaches to evaluate the role of Npr1 gene in the control of fluid volume, blood pressure, congestive heart failure, and other physiological function(s) and pathological states. The resulting knowledge should yield new molecular therapeutic targets for the treatment of hypertension and prevention of hypertension-related cardiovascular disorders. PUBLIC HEALTH RELEVANCE: High blood pressure is a growing problem in the modern world. More than 60 million Americans suffer from high blood pressure, which provokes kidney disease, heart failure, and stroke. Using Npr1 gene-targeted mutant mouse models, the research proposed in this application will provide new insights into the role of natriuretic peptide receptor-A in controlling blood pressure and hypertension. Moreover, this research project will elucidate the molecular mechanisms by which altered gene function may identify unique molecular targets that contribute towards the treatment and prevention of hypertension and related cardiovascular diseases. Information gained from the proposed studies will yield a more accurate assessment of the integrative and protective roles of atrial natriuretic peptide receptor gene and into possible mechanisms of pathogenesis whereby malregulation of receptor-mediated atrial natriuretic peptide bioactivity could result in abnormalities of fluid volume regulation and blood pressure homeostasis. Ultimately, this knowledge should yield new molecular therapeutic targets for the control and treatment of hypertension and cardiovascular diseases.